Prions are self-perpetuating protein aggregates that were first recognized in mammals for their role in a group of catastrophic and incurable neurodegenerative diseases known as the transmissible spongiform encephalopathies (TSEs). The discovery of a prion-like phenomenon in yeast has provided a powerful model system for the study of prion biology. Rather than killing the cell, yeast prions can confer on the cell new phenotypic traits that are propagated epigenetically. To date, no bacterial prions have been identified. However, this may simply reflect the difficulty of recognizing protein-based genetic elements in an organism that does not permit the detection of cytoplasmic inheritance; in bacteria, mating does not involve the transfer of cytoplasm. The objective of the proposed research is to develop a transcription-based assay for the conversion of protein domains to the prion state and to use such an assay as the basis for a genetic screen to identify prion-forming domains from bacteria and other organisms. The design of this assay will be informed by other transcription-based assays previously developed in the laboratory. The long-term goal of the proposed work is to mobilize bacterial genetics as a new tool to study the in vivo behavior of prion proteins, whether of bacterial origin or from eukaryotic cells. Ultimately, the use of genetically tractable model systems in both yeast and bacteria should provide insights that will be relevant to the understanding of the mammalian prion-based diseases.